Kupffer cells, the tissue fixed macrophage of the liver, are an essential part of the hepatic mechanisms for clearance and detoxification of gut derived endotoxin. Their orientation in the venous return from the bowel makes the Kupffer cell the first immune cell, beyond gut associated lymphoid tissue, to be exposed to absorbed ethanol and gut derived antigens. Absorption of ingested ethanol from the bowel and its detoxification by the liver may in the short term alter Kupffer cell responses to gut flora endotoxins, which may account for the state of immune suppression associated with ethanol intoxification. This project proposes to characterize the effects of acute ethanol toxicity on expression of the endotoxin responsive multifunctional cytokines interleukin-1, interleukin-6 and tumor necrosis factor by rat liver Kupffer cells. Physiologically, these proteins function in consort as regulators of normal cell function and have been implicated in the pathogenesis of hepatic disease. We will examine the effect of ethanol on the expression of these cytokines by northern blot analysis and specific ELISA. Experiments will be carried out to determine whether ethanol effects the transcription rate, message stability or the secondary proteins involved in the regulation of these genes. Ethanol has a demonstrated effect on signal transduction processes in the isolated hepatocyte. Some of these effects, elevation of cAMP levels or increased membrane associated protein kinase C activity, have been implicated in cytokine regulation. Experiments will be conducted to examine the effect of ethanol on Kupffer cell signal transduction mechanisms measured in terms of cytokine expression by northern blot analysis and ELISA. These studies should provide new insights into the role of the Kupffer cell in the immune suppression associated with chronic alcohol ingestion.